A ROS storm generating nanocomposite for enhanced chemodynamic therapy through H 2 O 2 self-supply, GSH depletion and calcium overload.

Catalytic generation of toxic hydroxyl radicals (˙OH) from hydrogen peroxide (H 2 O 2 ) is an effective strategy for tumor treatment in chemodynamic therapy (CDT). However, the intrinsic features of the microenvironment in solid tumors, characterized by limited H 2 O 2 and overexpressed glutathione (GSH), severely impede the accumulation of intracellular ˙OH, posing significant challenges. To circumvent these critical issues, in this work, a CaO 2 -based multifunctional nanocomposite with a surface coating of Cu 2+ and L-buthionine sulfoximine (BSO) (named CaO 2 @Cu-BSO) is designed for enhanced CDT. Taking advantage of the weakly acidic environment of the tumor, the nanocomposite gradually disintegrates, and the exposed CaO 2 nanoparticles subsequently decompose to produce H 2 O 2 , alleviating the insufficient supply of endogenous H 2 O 2 in the tumor microenvironment (TME). Furthermore, Cu 2+ detached from the surface of CaO 2 is reduced by H 2 O 2 and GSH to Cu + and ROS. Then, Cu + catalyzes H 2 O 2 to generate highly cytotoxic ˙OH and Cu 2+ , forming a cyclic catalysis effect for effective CDT. Meanwhile, GSH is depleted by Cu 2+ ions to eliminate possible ˙OH scavenging. In addition, the decomposition of CaO 2 by TME releases a large amount of free Ca 2+ , resulting in the accumulation and overload of Ca 2+ and mitochondrial damage in tumor cells, further improving CDT efficacy and accelerating tumor apoptosis. Besides, BSO, a molecular inhibitor, decreases GSH production by blocking γ-glutamyl cysteine synthetase. Together, this strategy allows for enhanced CDT efficiency via a ROS storm generation strategy in tumor therapy. The experimental results confirm and demonstrate the satisfactory tumor inhibition effect both in vitro and in vivo .